Our investigations are directed at the mechanisms of drug resistance and red blood cell invasion by the malaria parasite Plasmodium falciparum. Genetic crosses, linkage analysis, and differential screening, methods are being employed to characterize genes involved in these mechanisms. Resistance to two common antimalarial drugs, pyrimethamine and proguanil, has been found to result from point mutations in the P.falciparum dihydrofolate reductase gene. Different point mutations produce different responses to each drug, explaining why strains refractory to one drug may still respond to the other. Chloroquine resistance has been examined in a cross of two P. falciparum clones. Examination of 16 independent recombinant progeny from the cross indicates that chloroquine resistance is controlled by a single gene or by a closely linked group of genes. Linkage analysis studies are being performed to search for the locus controlling chloroquine resistance. Alternative pathways of red cell invasion are activated in some parasite clones when sialic acid residues are cleaved from the red cell surface by neuraminidase treatment. Differential and subtractive screening methods are being used to clone genes involved in these pathways.